A number of recent studies have demonstrated that most mice are actively undergoing an immune response to endogenous oncornaviruses. This is reflected by the presence of circulating antibodies in the sera of normal mice of high and low leukemic strains mouse-tropic and xeno-tropic MuLV's and by the presence of cytotoxic lymphocytes in the spleens of normal mice against leukemia-associated antigens. This widespread occurrence of immunity in the mouse against endogenous oncornaviruses and virus-associated antigens may be viewed as a paradox; it would be anticipated that lifelong continuous production of MuLV in mice of high leukemia strains would result in immunological tolerance against viral antigens. The purpose of this research project is to investigate further the parameters of immune response of the host to MuLV and leukemia-associated antigens. In the initial phase of this program we will consider a detailed description of the humoral and cellular compartments of natural immunity against leukemias, with the identification of antigenic specificities detected by the host. This analysis also will be directed at determining the efficacy of this immune response in respect to immune surveillance against spontaneous leukemogenesis. Genetic crosses that segregate for immune response, production of infectious MuLV, and spontaneous leukemogenesis will be used to determine relation between these phenomena. Subsequent analysis will lead to the isolation of viral and cell-associated antigens for chemical analysis and production of monospecific antisera. Purified antigens also will be used for immunization of mice to determine immunogenicity and potential protective effects against disease.